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http://en.wikipedia.org/wiki/Stem_cell
Stem cells are cells found in all multi-cellular organisms. They retain the ability to renew themselves through mitotic cell division and can differentiate into a diverse range of specialized cell types. Research in the stem cell field grew out of findings by Canadian scientists Ernest A. McCulloch and James E. Till in the 1960s.[1][2] The two broad types of mammalian stem cells are: embryonic stem cells that are found in blastocysts, and adult stem cells that are found in adult tissues. In a developing embryo, stem cells can differentiate into all of the specialized embryonic tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing specialized cells, but also maintain the normal turnover of regenerative organs, such as blood, skin or intestinal tissues.
As stem cells can be grown and transformed into specialized cells with characteristics consistent with cells of various tissues such as muscles or nerves through cell culture, their use in medical therapies has been proposed. In particular, embryonic cell lines, autologous embryonic stem cells generated through therapeutic cloning, and highly plastic adult stem cells from the umbilical cord blood or bone marrow are touted as promising candidates.[3]
Contents [hide]
1 Properties of Stem Cells
1.1 Potency definitions
1.2 Identifying Stem Cells
2 Embryonic stem cells
3 Adult stem cells
4 Lineage
5 Treatments
6 Controversy surrounding human embryonic stem cell research
7 Key stem cell research events
8 Stem cell funding & policy debate in the US
9 See also
10 References
11 External links
Properties of Stem Cells
The classical definition of a stem cell requires that it possess two properties:
Self-renewal - the ability to go through numerous cycles of cell division while maintaining the undifferentiated state.
Potency - the capacity to differentiate into specialized cell types. In the strictest sense, this requires stem cells to be either totipotent or pluripotent - to be able to give rise to any mature cell type, although multipotent or unipotent progenitor cells are sometimes referred to as stem cells.
Potency definitions
Pluripotent, embryonic stem cells originate as inner mass cells within a blastocyst. The stem cells can become any tissue in the body, excluding a placenta. Only the morula's cells are totipotent, able to become all tissues and a placenta.Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.
Totipotent stem cells are produced from the fusion of an egg and sperm cell. Cells produced by the first few divisions of the fertilized egg are also totipotent. These cells can differentiate into embryonic and extraembryonic cell types.
Pluripotent stem cells are the descendants of totipotent cells and can differentiate into cells derived from any of the three germ layers.
Multipotent stem cells can produce only cells of a closely related family of cells (e.g. hematopoietic stem cells differentiate into red blood cells, white blood cells, platelets, etc.).
Unipotent cells can produce only one cell type, but have the property of self-renewal which distinguishes them from non-stem cells (e.g. muscle stem cells).
Identifying Stem Cells
The practical definition of a stem cell is the functional definition - the ability to regenerate tissue over a lifetime. For example, the gold standard test for a bone marrow or hematopoietic stem cell (HSC) is the ability to transplant one cell and save an individual without HSCs. In this case, a stem cell must be able to produce new blood cells and immune cells over a long term, demonstrating potency. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.
Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, where single cells are characterized by their ability to differentiate and self-renew.[4][5] As well, stem cells can be isolated based on a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar manner in vivo. Considerable debate exists whether some proposed adult cell populations are truly stem cells.
Embryonic stem cells
Main article: Embryonic stem cell
Embryonic stem cell lines (ES cell lines) are cultures of cells derived from the epiblast tissue of the inner cell mass (ICM) of a blastocyst or earlier morula stage embryos.[6] A blastocyst is an early stage embryo—approximately four to five days old in humans and consisting of 50–150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.
Nearly all research to date has taken place using mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin and require the presence of Leukemia Inhibitory Factor (LIF).[7] Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic Fibroblast Growth Factor (bFGF or FGF-2).[8] Without optimal culture conditions or genetic manipulation,[9] embryonic stem cells will rapidly differentiate.
A human embryonic stem cell is also defined by the presence of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and SOX2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[10] The cell surface antigens most commonly used to identify hES cells are the glycolipids SSEA3 and SSEA4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.[11]
After twenty years of research, there are no approved treatments or human trials using embryonic stem cells. ES cells, being totipotent cells, require specific signals for correct differentiation - if injected directly into the body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[12] Many nations currently have moratoria on either ES cell research or the production of new ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.
Adult stem cells
Main article: Adult stem cell
Stem cell division and differentiation. A - stem cell; B - progenitor cell; C - differentiated cell; 1 - symmetric stem cell division; 2 - asymmetric stem cell division; 3 - progenitor division; 4 - terminal differentiationThe term adult stem cell refers to any cell which is found in a developed organism that has two properties: the ability to divide and create another cell like itself and also divide and create a cell more differentiated than itself. Also known as somatic (from Greek Σωματικóς, "of the body") stem cells and germline (giving rise to gametes) stem cells, they can be found in children, as well as adults.[13] Pluripotent adult stem cells are rare and generally small in number but can be found in a number of tissues including umbilical cord blood.[14] Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, etc.).[15][16]
A great deal of adult stem cell research has focused on clarifying their capacity to divide or self-renew indefinitely and their differentiation potential.[17] In mice, pluripotent stem cells are directly generated from adult fibroblast cultures.[18]
While embryonic stem cell potential remains untested, adult stem cell treatments have been used for many years to treat successfully leukemia and related bone/blood cancers through bone marrow transplants.[19] The use of adult stem cells in research and therapy is not as controversial as embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Consequently, more US government funding is being provided for adult stem cell research.[20]
Lineage
Main article: Stem cell line
To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.[21]
An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals dpp and adherins junctions that prevent germarium stem cells from differentiating.[22][23]
Main article: Induced Pluripotent Stem Cell
The signals that lead to reprogramming of cells to an embryonic-like state are also being investigated. These signal pathways include several transcription factors including the oncogene c-Myc. Initial studies indicate that transformation of mice cells with a combination of these anti-differentiation signals can reverse differentiation and may allow adult cells to become pluripotent.[24] However, the need to transform these cells with an oncogene may prevent the use of this approach in therapy.
Treatments
Main article: Stem cell treatments
Medical researchers believe that stem cell therapy has the potential to change radically the treatment of human disease. A number of adult stem cell therapies already exist, particularly bone marrow transplants that are used to treat leukemia.[25] In the future, medical researchers anticipate being able to use technologies derived from stem cell research to treat a wider variety of diseases including cancer, Parkinson's disease, spinal cord injuries, and muscle damage, amongst a number of other impairments and conditions.[26][27] However, there still exists a great deal of social and scientific uncertainty surrounding stem cell research, which could possibly be overcome through public debate and future research.
Stem cells, however, are already used extensively in research, and some scientists do not see cell therapy as the first goal of the research, but see the investigation of stem cells as a goal worthy in itself.[28]
Controversy surrounding human embryonic stem cell research
Main article: Stem cell controversy
There exists a widespread controversy over human embryonic stem cell research that emanates from the techniques used in the creation and usage of stem cells. Human embryonic stem cell research is controversial because, with the present state of technology, starting a stem cell line requires the destruction of a human embryo and/or therapeutic cloning. However, recently, it has been shown in principle that embryonic stem cell lines can be generated using a single-cell biopsy similar to that used in preimplantation genetic diagnosis that may allow stem cell creation without embryonic destruction.[29] It is not the entire field of stem cell research, but the specific field of human embryonic stem cell research that is at the centre of an ethical debate.
Opponents of the research argue that embryonic stem cell technologies are a slippery slope to reproductive cloning and can fundamentally devalue human life. Those in the pro-life movement argue that a human embryo is a human life and is therefore entitled to protection.
Contrarily, supporters of embryonic stem cell research argue that such research should be pursued because the resultant treatments could have significant medical potential. It is also noted that excess embryos created for in vitro fertilisation could be donated with consent and used for the research.
The ensuing debate has prompted authorities around the world to seek regulatory frameworks and highlighted the fact that stem cell research represents a social and ethical challenge.
Key stem cell research events
1960s - Joseph Altman and Gopal Das present scientific evidence of adult neurogenesis, ongoing stem cell activity in the brain; their reports contradict Cajal's "no new neurons" dogma and are largely ignored.
1963 - McCulloch and Till illustrate the presence of self-renewing cells in mouse bone marrow.
1968 - Bone marrow transplant between two siblings successfully treats SCID.
1978 - Haematopoietic stem cells are discovered in human cord blood.
1981 - Mouse embryonic stem cells are derived from the inner cell mass by scientists Martin Evans, Matthew Kaufman, and Gail R. Martin. Gail Martin is attributed for coining the term "Embryonic Stem Cell".
1992 - Neural stem cells are cultured in vitro as neurospheres.
1997 - Leukemia is shown to originate from a haematopoietic stem cell, the first direct evidence for cancer stem cells.
1998 - James Thomson and coworkers derive the first human embryonic stem cell line at the University of Wisconsin-Madison.
2000s - Several reports of adult stem cell plasticity are published.
2001 - Scientists at Advanced Cell Technology clone first early (four- to six-cell stage) human embryos for the purpose of generating embryonic stem cells.[30]
2003 - Dr. Songtao Shi of NIH discovers new source of adult stem cells in children's primary teeth.[31]
2004-2005 - Korean researcher Hwang Woo-Suk claims to have created several human embryonic stem cell lines from unfertilised human oocytes. The lines were later shown to be fabricated.
2005 - Researchers at Kingston University in England claim to have discovered a third category of stem cell, dubbed cord-blood-derived embryonic-like stem cells (CBEs), derived from umbilical cord blood. The group claims these cells are able to differentiate into more types of tissue than adult stem cells.
August 2006 - Rat Induced pluripotent stem cells: the journal Cell publishes Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors".
October 2006 - Scientists in England create the first ever artificial liver cells using umbilical cord blood stem cells.[32][33]
January 2007 - Scientists at Wake Forest University led by Dr. Anthony Atala and Harvard University report discovery of a new type of stem cell in amniotic fluid.[5] This may potentially provide an alternative to embryonic stem cells for use in research and therapy.[34]
June 2007 - Research reported by three different groups shows that normal skin cells can be reprogrammed to an embryonic state in mice.[35] In the same month, scientist Shoukhrat Mitalipov reports the first successful creation of a primate stem cell line through somatic cell nuclear transfer[36]
October 2007 - Mario Capecchi, Martin Evans, and Oliver Smithies win the 2007 Nobel Prize for Physiology or Medicine for their work on embryonic stem cells from mice using gene targeting strategies producing genetically engineered mice (known as knockout mice) for gene research.[37]
November 2007 - Human Induced pluripotent stem cells: Two similar papers released by their respective journals prior to formal publication: in Cell by Kazutoshi Takahashi and Shinya Yamanaka, "Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors", and in Science by Junying Yu, et al., from the research group of James Thomson, "Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells": pluripotent stem cells generated from mature human fibroblasts. It is possible now to produce a stem cell from almost any other human cell instead of using embryos as needed previously, albeit the risk of tumorigenesis due to c-myc and retroviral gene transfer remains to be determined.
January 2008 - Human embryonic stem cell lines were generated without destruction of the embryo[38]
January 2008 - Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts[39]
Stem cell funding & policy debate in the US
This article's coverage of a controversial issue may be inaccurate or unbalanced in favor of certain viewpoints.
Please improve the article by adding information on neglected viewpoints, or discuss the issue on the talk page.
1995 - U.S. President Bill Clinton signs into law the Dickey Amendment which prohibited federally appropriated funds to be used for research where human embryos would be either created or destroyed.
02 November, 2004 - California voters approve Proposition 71, which provides $3 billion in state funds over ten years to human embryonic stem cell research.
2001-2006 - U.S. President George W. Bush endorses the Congress in providing federal funding for embryonic stem cell research of approximately $100 million as well as $250 million for research on adult and animal stem cells. He also enacts laws that restrict federally-funded stem cell research on embryonic stem cells to the already derived cell lines.
5 May, 2006 - Senator Rick Santorum introduces bill number S. 2754, or the Alternative Pluripotent Stem Cell Therapies Enhancement Act, into the U.S. Senate.
18 July, 2006 - The U.S. Senate passes the Stem Cell Research Enhancement Act H.R. 810 and votes down Senator Santorum's S. 2754.
19 July, 2006 - President George W. Bush vetoes H.R. 810 (Stem Cell Research Enhancement Act), a bill that would have reversed the Clinton-era law which made it illegal for federal money to be used for research where stem cells are derived from the destruction of an embryo.
07 November, 2006 - The people of the U.S. state of Missouri passed Amendment 2, which allows usage of any stem cell research and therapy allowed under federal law, but prohibits human reproductive cloning.[40]
16 February, 2007 – The California Institute for Regenerative Medicine became the biggest financial backer of human embryonic stem cell research in the United States when they awarded nearly $45 million in research grants.[41]
See also
The American Society for Cell Biology
California Institute for Regenerative Medicine
Genetics Policy Institute
Cancer stem cells
Induced Pluripotent Stem Cell (iPS Cell)
References
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^ Tuch BE (2006). "Stem cells--a clinical update". Australian family physician 35 (9): 719-21. PMID 16969445.
^ Friedenstein AJ, Deriglasova UF, Kulagina NN, Panasuk AF, Rudakowa SF, Luria EA, Ruadkow IA (1974). "Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method". Exp Hematol 2 (2): 83-92. PMID 4455512.
^ Friedenstein AJ, Gorskaja JF, Kulagina NN (1976). "Fibroblast precursors in normal and irradiated mouse hematopoietic organs". Exp Hematol 4 (5): 267-74. PMID 976387.
^ http://www.foxnews.com/story/0,2933,210078,00.html
^ [1] , Mouse Embryonic Stem (ES) Cell Culture-Current Protocols in Molecular Biology
^ [2], Culture of Human Embryonic Stem Cells (hESC) NIH
^ Chambers I, Colby D, Robertson M, et al (2003). "Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells". Cell 113 (5): 643-55. doi:10.1016/S0092-8674(03)00392-1. PMID 12787505.
^ Boyer LA, Lee TI, Cole MF, et al (2005). "Core transcriptional regulatory circuitry in human embryonic stem cells". Cell 122 (6): 947-56. doi:10.1016/j.cell.2005.08.020. PMID 16153702.
^ Adewumi O, Aflatoonian B, Ahrlund-Richter L, et al (2007). "Characterization of human embryonic stem cell lines by the International Stem Cell Initiative". Nat. Biotechnol. 25 (7): 803-16. doi:10.1038/nbt1318. PMID 17572666.
^ Wu DC, Boyd AS, Wood KJ (2007). "Embryonic stem cell transplantation: potential applicability in cell replacement therapy and regenerative medicine". Front. Biosci. 12: 4525-35. doi:10.2741/2407. PMID 17485394.
^ Jiang Y, Jahagirdar BN, Reinhardt RL, et al (2002). "Pluripotency of mesenchymal stem cells derived from adult marrow". Nature 418 (6893): 41-9. doi:10.1038/nature00870. PMID 12077603.
^ Ratajczak MZ, Machalinski B, Wojakowski W, Ratajczak J, Kucia M (2007). "A hypothesis for an embryonic origin of pluripotent Oct-4(+) stem cells in adult bone marrow and other tissues". Leukemia 21 (5): 860-7. doi:10.1038/sj.leu.2404630. PMID 17344915.
^ Barrilleaux B, Phinney DG, Prockop DJ, O'Connor KC (2006). "Review: ex vivo engineering of living tissues with adult stem cells". Tissue Eng. 12 (11): 3007-19. doi:10.1089/ten.2006.12.3007. PMID 17518617.
^ Gimble JM, Katz AJ, Bunnell BA (2007). "Adipose-derived stem cells for regenerative medicine". Circ. Res. 100 (9): 1249-60. doi:10.1161/01.RES.0000265074.83288.09. PMID 17495232.
^ Gardner RL (2002). "Stem cells: potency, plasticity and public perception". Journal of Anatomy 200 (3): 277-82. doi:10.1046/j.1469-7580.2002.00029.x. PMID 12033732.
^ Takahashi K, Yamanaka S (2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell 126 (4): 663-76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
^ [3], Bone Marrow Transplant
^ [4],USDHHS Stem Cell FAQ 2004
^ Beckmann J, Scheitza S, Wernet P, Fischer JC, Giebel B (2007). "Asymmetric cell division within the human hematopoietic stem and progenitor cell compartment: identification of asymmetrically segregating proteins". Blood 109 (12): 5494-501. doi:10.1182/blood-2006-11-055921. PMID 17332245.
^ Xie T, Spradling A (1998). "decapentaplegic is essential for the maintenance and division of germline stem cells in the Drosophila ovary". Cell 94 (2): 251-60. doi:10.1016/S0092-8674(00)81424-5. PMID 9695953.
^ Song X, Zhu C, Doan C, Xie T (2002). "Germline stem cells anchored by adherens junctions in the Drosophila ovary niches.". Science 296 (5574): 1855-7. doi:10.1126/science.1069871. PMID 12052957.
^ Takahashi K, Yamanaka S (2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell 126 (4): 663-76. doi:10.1016/j.cell.2006.07.024. PMID 16904174.
^ Gahrton G, Björkstrand B (2000). "Progress in haematopoietic stem cell transplantation for multiple myeloma". J Intern Med 248 (3): 185-201. doi:10.1046/j.1365-2796.2000.00706.x. PMID 10971785.
^ Lindvall O (2003). "Stem cells for cell therapy in Parkinson's disease". Pharmacol Res 47 (4): 279-87. doi:10.1016/S1043-6618(03)00037-9. PMID 12644384.
^ Goldman S, Windrem M (2006). "Cell replacement therapy in neurological disease". Philos Trans R Soc Lond B Biol Sci 361 (1473): 1463-75. doi:10.1098/rstb.2006.1886. PMID 16939969.
^ Wade N (2006-08-14). Some Scientists See Shift in Stem Cell Hopes. New York Times. Retrieved on 2006-12-28.
^ http://www.npr.org/templates/story/story.php?storyId=5696557
^ http://www.sciam.com/article.cfm?articleID=0008B8F9-AC62-1C75-9B81809EC588EF21&pageNumber=4&catID=4
^ Shostak S (2006). "(Re)defining stem cells". Bioessays 28 (3): 301-8. doi:10.1002/bies.20376. PMID 16479584.
^ http://discovermagazine.com/2007/mar/good-news-for-alcoholics
^ http://news.scotsman.com/health.cfm?id=1608072006
^ http://www.boston.com/news/local/massachusetts/articles/2007/01/07/amniotic_fluid_yields_stem_cells_harvard_researchers_report/
^ Cyranoski D (2007). "Simple switch turns cells embryonic". Nature 447 (7145): 618-9. PMID 17554270.
^ Mitalipov SM, Zhou Q, Byrne JA, Ji WZ, Norgren RB, Wolf DP (2007). "Reprogramming following somatic cell nuclear transfer in primates is dependent upon nuclear remodeling". Hum Reprod 22 (8): 2232-42. PMID 17562675.
^ The Nobel Prize in Physiology or Medicine 2007. Nobelprize.org. Retrieved on 8 October 2007.
^ http://www.cellstemcell.com/content/article/abstract?uid=PIIS193459090700330X
^ http://stemcells.alphamedpress.org/cgi/reprint/2007-0252v1.pdf
^ Full-text of Missouri Constitution Amendment 2
^ Calif. Awards $45M in Stem Cell Grants Associated Press, Feb. 17, 2007.
External links
General
Tell Me About Stem Cells: Quick and simple guide explaining the science behind stem cells
Stem Cell Basics
Understanding Stem Cells: A View of the Science and Issues from the National Academies
Scientific American Magazine (June 2004 Issue) The Stem Cell Challenge
Scientific American Magazine (July 2006 Issue) Stem Cells: The Real Culprits in Cancer?
National Institutes of Health
Stem Cell Research Forum of India
Peer-reviewed journals
STEM CELLS®
Cytotherapy
Cloning and Stem Cells
Stem Cells and Development
Regenerative Medicine
Isolation of amniotic stem cell lines with potential for therapy
A cancer stem cell is a hypothetical type of stem cell which would form tumours while having stem cell properties such as self-renewal and the ability to differentiate into multiple cell types. A theory suggests such cells persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumours. Development of specific therapies targeted at cancer stem cells holds hope for improvement of survival and quality of life of cancer patients, especially for sufferers of metastatic disease.
Stem cell specific and conventional cancer therapiesExisting cancer treatments were mostly developed on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study.
The efficacy of cancer treatments are, in the initial stages of testing, often measured by the amount of tumour mass they kill off. As cancer stem cells would form a very small proportion of the tumour, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of cancer stem cells, which gave rise to it, could remain untouched and cause a relapse of the disease.
Contents [hide]
1 Evidence for cancer stem cells
1.1 Importance of stem cells
1.2 Mechanistic and mathematical models
2 Where do cancer stem cells come from?
3 Implications on Cancer Treatment
4 Cancer stem cell pathways
4.1 Bmi-1
4.2 Notch
4.3 Sonic hedgehog and Wnt
5 External links
6 References
[edit] Evidence for cancer stem cells
Opponents of the paradigm do not deny the existence of cancer stem cells as such. Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required for carcinogenesis, and to sustain the growth of a tumor since differentiated cells cannot divide indefinitely (constrained by the Hayflick Limit). However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties there is no incentive to focusing on a specific subpopulation. There is also debate on the cell of origin of these cancer stem cells - whether they originate from stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity).
The first conclusive evidence for cancer stem cells was published in 1997 in Nature Medicine. Bonnet and Dick[1] isolated a subpopulation of leukaemic cells that express a specific surface marker CD34, but lacks the CD38 marker. The authors established that the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that is histologically similar to the donor. (Matsui, 2004)
In cancer research experiments, tumor cells are sometimes injected into an experimental animal to establish a tumor. Disease progression is then followed in time and novel drugs can be tested for their ability to inhibit it. However, efficient tumor formation requires thousands or tens of thousands of cells to be introduced. Classically, this has been explained by poor methodology (i.e. the tumor cells lose their viability during transfer) or the critical importance of the microenvironment, the particular biochemical surroundings of the injected cells. Supporters of the cancer stem cell paradigm argue that only a small fraction of the injected cells, the cancer stem cells, have the potential to generate a tumor. In human acute myeloid leukemia the frequency of these cells is less than 1 in 10,000.[1]
Further evidence comes from histology, the study of tissue structure of tumors. Many tumors are very heterogeneous and contain multiple cell types native to the host organ. Heterogeneity is commonly retained by tumor metastases. This implies that the cell that produced them had the capacity to generate multiple cell types. In other words, it possessed multidifferentiative potential, a classical hallmark of stem cells.[1]
The existence of leukaemic stem cells prompted further research into other types of cancer. Cancer stem cells have recently been identified in several solid tumours, including:
Breast cancer[2]
Brain cancer[3]
Colon cancers[4]
Pancreatic cancer[5]
Ovarian cancer[6]
[edit] Importance of stem cells
Not only is finding the source of cancer cells necessary for succssful treatments, but if current treatments of cancer do not properly destroy enough cancer stem cells, the tumor will reappear. Including the possibility that the treatment of for instance, chemotherapy, will leave only chemotherapy-resistant cancer stem cells, then the ensuing tumor will most likely also be resistant to chemotherapy. If the cancer tumor is detected early enough, enough of the tumor can be killed off and marginalized with traditional treatment. But as the tumor size increases, it becomes more and more difficult to remove the tumor without conferring resistance and leaving enough behind for the tumor to reappear.
Some treatments with chemotherapy, such as paclitaxel in ovarian cancer (a cancer usually discovered in late stages), may actually serve to promote certain cancer growth (55-75% relapse <2 years[7]). It potentially does this by destroying only the cancer cells susceptible to the drug (targeting those that are CD44-positive, a trait which has been associated with increased survival time in some ovarian cancers), and allowing the cells which are unaffected by paclitaxel (CD44-negative) to regrow, even after a reduction in over a third of the total tumor size.[6] There are studies, though, which show how paclitaxel can be used in combination with other ligands to affect the CD44-positive cells.[8] While paclitaxel alone, as of late, does not cure the cancer, it is effective at extending the survival time of the patients.[7]
[edit] Mechanistic and mathematical models
Once the pathways to cancer are hypothesized, it is possible to develop predictive mathematical biology models,[9] e.g., based on the cell compartment method. For instance, the growths of the abnormal cells from their normal counterparts can be denoted with specific mutation probabilities. Such a model has been employed to predict that repeated insult to mature cells increases the formation of abnormal progeny, and hence the risk of cancer.[10] Considerable work needs to be done, however, before the clinical efficacy of such models is established.
[edit] Where do cancer stem cells come from?
This is still an area of ongoing research. Logically, the smallest change (and hence the most likely mutation) to produce a cancer stem cell would be a mutation from a normal stem cell. Also, in tissues with a high rate of cell turnover (such as the skin or GI epithelium, where cancers are common), it can be argued that stem cells are the only cells that live long enough to acquire enough genetic abnormalities to become cancerous. However it is still possible that more differentiated cancer cells (in which the genome is less stable) could acquire properties of 'stemness'.
It is likely that in a tumour there are several lines of stem cells, with new ones being created and others dying off as a tumour grows and adapts to its surroundings.[11] Hence, tumour stem cells can constitute a 'moving target', making them even harder to treat.
[edit] Implications on Cancer Treatment
The existence of cancer stem cells have several implications in terms of future cancer treatment and therapies. These include disease identification, selective drug targets, prevention of metastasis, and development of new strategies in fighting cancer.
Normal somatic stem cells are naturally resistant to chemotherapeutic agents - they have various pumps (such as MDR) that pump out drugs, DNA repair proteins and they also have a slow rate of cell turnover (chemotherapeutic agents naturally target rapidly replicating cells). Cancer stem cells, being the mutated counterparts of normal stem cells, may also have similar functions which allows them to survive therapy. These surviving cancer stem cells then repopulates the tumour, causing relapse. By selectively targeting cancer stem cells, it would be possible to treat patients with aggressive, non-resectable tumours, as well as preventing the tumour from metastasizing. The hypothesis infers that if the cancer stem cells are eliminated, the cancer would simply regress due to differentiation and cell death.
There has also been a lot of research into finding specific markers which may distinguish cancer stem cells from the bulk of the tumour (as well as from normal stem cells), with some success.[12] Proteomic and genomic signatures of tumours are also being investigated. Success in these area would enable faster identification of tumour subtypes, as well as enable personalized medicine in cancer treatments by using the right combination of drugs and/or treatments to efficiently eliminate the tumour.
[edit] Cancer stem cell pathways
A normal stem cell may be transformed into a cancer stem cell through disregulation of the proliferation and differentiation pathways controlling it. Scientists working on cancer stem cells hope to design new drugs targeting these cellular mechanisms. The first findings in this area were made using haematopoietic stem cells (HSCs) and their transformed counterparts in leukemia, the disease whose stem cell origin is most strongly established. However, these pathways appear to be shared by stem cells of all organs.
[edit] Bmi-1
The Polycomb group transcriptional repressor Bmi-1 was discovered as a common oncogene activated in lymphoma[13] and later shown to specifically regulate HSCs.[14] The role of Bmi-1 has also been illustrated in neural stem cells.[15] The pathway appears to be active in cancer stem cells of pediatric brain tumors.[16]
[edit] Notch
The Notch pathway has been known to developmental biologists for decades. Its role in control of stem cell proliferation has now been demonstrated for several cell types including haematopoietic, neural and mammary[17] stem cells. Components of the Notch pathway have been proposed to act as oncogenes in mammary[18] and other tumors.
[edit] Sonic hedgehog and Wnt
These developmental pathways are also strongly implicated as stem cell regulators.[19] Both Sonic hedgehog(SHH) and Wnt pathways are commonly hyperactivated in tumors and are required to sustain tumor growth. However, the Gli transcription factors that are regulated by SHH take their name from gliomas, where they are commonly expressed at high levels. A degree of crosstalk exists between the two pathways and their activation commonly goes hand-in-hand.[20] This is a trend rather than a rule. For instance, in colon cancer hedgehog signalling appears to antagonise Wnt.[21]
Sonic hedgehog blockers are available, such as cyclopamine. There is also a new water soluble cyclopamine that may be more effective in cancer treatment. There is also DMAPT, a water soluble derivative of parthenolide that targets AML (leukemia) stem cells, and possibly other cancer stem cells as in myeloma or prostate cancer. A clinical trial of DMAPT is to start in England in late 2007 or 2008. Furthermore, GRN163L was recently started in trials to target myeloma stem cells. If it is possible to eliminate the cancer stem cell, than a potential cure may be achieved if there are no more cancer stem cells to repopulate a cancer.
[edit] External links
"Cancer Stem Cell Scientific Literature Review", UMDNJ Stem Cell Research and Regenerative Medicine, June 17, 2006
"Stem cells may cause some forms of bone cancer", News-Medical.Net, December 7, 2005
"The Bad Seed: Rare stem cells appear to drive cancers", Science News Online, March 20, 2004
"The Real Problem in Breast Tumors: Cancer Stem Cells", Genome News Network, March 7, 2003
[1] Stem Cell and Cord Blood information database
[edit] References
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^ Al-Hajj et al. (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100(7):3983-8. Entrez PubMed 12629218
^ Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res. 63:5821-8. Entrez PubMed 14522905
^ O'Brien CA, Pollett A, Gallinger S, Dick JE. (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 445:106-10. Entrez PubMed 17122772
^ Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM. Identification of Pancreatic Cancer Stem Cells. Cancer Res. 2007 Feb 1;67(3):1030-7.
^ a b Mor, G. Yale Medical School. Presentation of unpublished data at University of Missour, Kansas City Medical School. Jan 7, 2008.
^ a b England's National Institute of Health and Clinical Excellence. Full guidance on the use of paclitaxel in the treatment of ovarian cancer, 22 January 2003.
^ Edmond Auzenne, Sukhen C Ghosh, Mojgan Khodadadian, Belinda Rivera, David Farquhar, Roger E Price, Murali Ravoori, Vikas Kundra, Ralph S Freedman, and Jim Klostergaard. [Hyaluronic Acid-Paclitaxel: Antitumor Efficacy against CD44(+) Human Ovarian Carcinoma Xenografts http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1899257]. Neoplasia. 2007 June; 9(6): 479–486.
^ Preziosi, L. (2003) Cancer Modelling and Simulation. Chapman Hall/CRC Press. ISBN 1-58488-361-8.
^ Ganguly R. and Puri I.K. (2006) Mathematical model for the cancer stem cell hypothesis. Cell Prolif 39:3-14. Entrez PubMed 16426418.
^ Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL and Wahl GM. (2006) Cancer Stem Cells--Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells. Cancer Research 39:3-14. Entrez PubMed 16990346.
^ Al-Hajj et al. (2003) Prospective identification of tumorigenic breast cancer cells. Nat Med 3:730-7. Entrez PubMed 12629218 12629218
^ Haupt Y, Bath ML, Harris AW and Adams JM. (1993) bmi-1 transgene induces lymphomas and collaborates with myc in tumorigenesis. Oncogene, 8:3161-4. Entrez PubMed 8414519.
^ Park IK, Qian D, Kiel M, Becker MW, Pihalja M, Weissman IL, Morrison SJ and Clarke MF. (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature, 423:302-5. Entrez PubMed 12714971.
^ Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF and Morrison SJ. (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature, 425:962-7. Entrez PubMed 14574365.
^ Hemmati HD, Nakano I, Lazareff JA, Masterman-Smith M, Geschwind DH, Bronner-Fraser M and Kornblum HI. (2003) Cancerous stem cells can arise from pediatric brain tumors. PNAS 100:15178-83. Full text at PMC: 299944
^ Dontu G, Jackson KW, McNicholas E, Kawamura MJ, Abdallah WM, Wicha MS. (2004) Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6:R605-15. Full text at PMC: 1064073
^ Dievart A, Beaulieu N and Jolicoeur P. (1999) Involvement of Notch1 in the development of mouse mammary tumors. Oncogene. 18:5973-81. Entrez PubMed 10557086
^ Beachy PA, Karhadkar SS and Berman DM. (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature. 432:324-31. Entrez PubMed 15549094
^ Zhou BP and Hung MC. (2005) Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis. Cell Cycle. 4:772-6. Entrez PubMed 15917668
^ Akiyoshi T, Nakamura M, Koga K, Nakashima H, Yao T, Tsuneyoshi M, Tanaka M and Brian McDonald. (2005) Gli1, down-regulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation. Gut. [Epub ahead of print]. Entrez PubMed 16299030